Technical field
The present discovery pertains generally to the field of cosmetic and therapeutic compounds. More specifically the invention pertains to certain 1-dialkylphosphorylalkanes, as described herein as “Dapa compounds” that are useful, for example, in the treatment of disorders (e.g., diseases) of sebocyte function, including: acne, seborrheic dermatitis, and “oily skin”, and other disorders of cellular proliferation. The present invention also pertains to topical dermatological compositions formulated to deliver the Dapa compounds, and the use of such compounds and compositions, for example, in cosmetic therapy or in dermatological therapy.
Description of Related Art
Rowsell and Spring [Phosphine oxides having a physiological cooling effect. U.S. Pat. No. 4,070,496. 1978] described trialkylphosphine oxides to have a “physiological cooling action”.
The pilosebaceous unit [PSU] is an epidermal invagination found on most surfaces of the human body and consists of a hair follicle, a sebaceous gland, and an arrector pili muscle. The sebaceous glands produce an oily/waxy substance called sebum which is extruded into the hair follicle and then onto the surface of the skin. The PSU is distributed throughout the skin except for the palms and soles, and the density of PSU is especially high in the scalp, face, and upper body. Sebaceous glands are also found in non-haired areas [glabrous skin] of eyelids, nose, penis, labia minora and nipples [Hinde. et al. A practical guide for the study of human and murine sebaceous glands in situ. Exp. Dermatol. 22, 631-7 (2013)].
The principal cell of the sebaceous gland is the sebocyte. When sebocytes mature and burst [holocrine secretion], the cell constituents form sebum which is mostly lipids such as triglycerides, free fatty acids, wax esters, squalene, and cholesterol and cholesterol esters, and other cellular products [Picardo et al. Sebaceous gland lipids. Dermatoendocrinol. 1, 68-71 (2009)]. The sebum protects the skin against excessive hydration and helps regulate body temperature.
Sebum dysfunction is associated with acne, oily skin, and skin disorders such as seborrheic dermatitis [Zouboulis. Acne and sebaceous gland function. Clin. Dermatol. 22, 360-6 (2004)]. These conditions have a high prevalence [e.g. for acne, ˜14 million office visits per year in the US; for oily skin a ˜26% prevalence in Chinese women, confirmed by Sebumeter® measurements] and are associated with a perceived decrease in quality of life [Nouveau-Richard et al. Oily skin: specific features in Chinese women. Skin research and technology: 13, 43-8 (2007); Wu et al. A preliminary investigation of the impact of oily skin on quality of life and concordance of self-perceived skin oiliness and skin surface lipids (sebum). Int. J. Cosmet. Sci. 35, 442-7 (2013)]. Currently, the only drugs that directly target sebocyte function are the androgen receptor antagonists, e.g. cyproterone acetate, and possibly isotretinoin. Antagonists of melanocortin receptor 5 have been proposed, but have not yet reached the clinic [Zhang et al. Melanocortin-5 receptor and sebogenesis. Eur. J. Pharmacol. 660, 202-6 (2011)].
Acne, oily skin, and seborrheic dermatitis affect the appearance of the facial skin and are a source of embarrassment and distress. The major pathogenic factor promoting acne is increased sebum production from the pilosebaceous unit [PSU] caused by androgen action on seboycytes. Other factors in pathogenesis are ductal hypercornification, colonization of the PSU by Propionibacterium acnes, and inflammation [Cunliffe et al. Comedone formation: etiology, clinical presentation, and treatment. Clin. Dermatol. 22, 367-74 (2004)]. Oily skin [seborrhea] is a common cosmetic problem that occurs when oversized sebaceous glands produce excessive amounts of sebum giving the appearance of shiny and greasy skin. Seborrheic dermatitis is characterized by red, flaking, greasy areas of skin, most commonly on the scalp, nasolabial folds, ears, eyebrows and chest. The prevalence of seborrheic dermatitis is not precise but may affect up to 1 to 5% of the adult population [Schwartz et al. Seborrheic dermatitis: an overview. Am. Fam. Physician 74, 125-30 (2006)].
A therapeutic agent that interferes with sebocyte function and reduce sebum secretion will have benefits in disorders of sebum function such as acne, oily skin, and seborrheic dermatitis.